Resolving the fibrotic niche of human liver cirrhosis at single-cell level

Ramachandran P.; Dobie R.; Wilson-Kanamori J. R.; Dora E. F.; Henderson B. E. P.; Luu N. T.; Portman J. R.; Matchett K. P.; Brice M.; Marwick J. A.; Taylor R. S.; Efremova M.; Vento-Tormo R.; Carragher N. O.; Kendall T. J.; Fallowfield J. A.; Harrison E. M.; Mole D. J.; Wigmore S. J.; Newsome P. N.; Weston C. J.; Iredale J. P.; Tacke F.; Pollard J. W.; Ponting C. P.; Marioni J. C.; Teichmann S. A.; Henderson N. C.

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Resolving the fibrotic niche of human liver cirrhosis at single-cell level

机译：在单细胞水平上解决人肝硬化的纤维化生态位

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Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2(+)CD9(+) subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1(+) and PLVAP(+) endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFR alpha(+) collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.

机译：肝硬化是全世界主要的死亡原因，其特征是广泛的纤维化。当前没有有效的抗纤维化疗法。为了更好地了解疾病发病机理中涉及的细胞和分子机制，并发现治疗靶标，在这里我们分析了超过100,000个单个人类细胞的转录组，从而得出了健康人群中非实质细胞类型的分子定义。和肝硬化的人肝。我们发现巨噬细胞的疤痕相关的TREM2（+）CD9（+）亚群，在肝纤维化中扩展，从循环单核细胞分化，并且是促纤维化的。我们还定义了在肝硬化中扩展的ACKR1（+）和PLVAP（+）内皮细胞，在地形上受限于纤维化小生境，并增强了白细胞的转运。瘢痕相关巨噬细胞，内皮细胞和PDGFR alpha（+）胶原生成间充质细胞之间的配体和受体相互作用的多谱系建模揭示了包括TNFRSF12A，PDGFR和NOTCH信号传导在内的几种促纤维化途径的瘢痕内活性。我们的工作在单细胞水平上剖析了人体器官纤维化的细胞和分子基础的未曾预料到的方面，并为发现肝硬化中合理的治疗靶标提供了概念框架。

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《Nature》 |2019年第7783期|512-518|共7页
作者
Ramachandran P.; Dobie R.; Wilson-Kanamori J. R.; Dora E. F.; Henderson B. E. P.; Luu N. T.; Portman J. R.; Matchett K. P.; Brice M.; Marwick J. A.; Taylor R. S.; Efremova M.; Vento-Tormo R.; Carragher N. O.; Kendall T. J.; Fallowfield J. A.; Harrison E. M.; Mole D. J.; Wigmore S. J.; Newsome P. N.; Weston C. J.; Iredale J. P.; Tacke F.; Pollard J. W.; Ponting C. P.; Marioni J. C.; Teichmann S. A.; Henderson N. C.;
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Univ Edinburgh Queens Med Res Inst Edinburgh BioQuarter Ctr Inflammat Res Edinburgh Midlothian Scotland;

Univ Hosp Birmingham NHS Fdn Trust NIHR Birmingham Biomed Res Ctr Birmingham W Midlands England|Univ Birmingham Birmingham W Midlands England|Univ Birmingham Inst Immunol & Immunotherapy Birmingham W Midlands England;

Univ Edinburgh Queens Med Res Inst Edinburgh BioQuarter Ctr Inflammat Res Edinburgh Midlothian Scotland|Univ Edinburgh Inst Genet & Mol Med MRC Canc Res UK Edinburgh Ctr Edinburgh Midlothian Scotland;

Wellcome Sanger Inst Wellcome Genome Campus Cambridge England;

Univ Edinburgh Inst Genet & Mol Med MRC Canc Res UK Edinburgh Ctr Edinburgh Midlothian Scotland;

Univ Edinburgh Queens Med Res Inst Edinburgh BioQuarter Ctr Inflammat Res Edinburgh Midlothian Scotland|Univ Edinburgh Div Pathol Edinburgh Midlothian Scotland;

Univ Edinburgh Royal Infirm Edinburgh Clin Surg Edinburgh Midlothian Scotland;

Univ Edinburgh Queens Med Res Inst Edinburgh BioQuarter Ctr Inflammat Res Edinburgh Midlothian Scotland|Univ Edinburgh Royal Infirm Edinburgh Clin Surg Edinburgh Midlothian Scotland;

Biomed Res Ctr Off Vice Chancellor Beacon House & Natl Inst Hearth Res Bristol Avon England;

Charite Dept Hepatol & Gastroenterol Med Ctr Berlin Germany;

Univ Edinburgh Ctr Reprod Hlth Queens Med Res Inst MRC Edinburgh Midlothian Scotland|Albert Einstein Coll Med Dept Dev & Mol Biol New York NY USA;

Univ Edinburgh Inst Genet & Mol Med MRC Human Genet Unit Edinburgh Midlothian Scotland;

Wellcome Sanger Inst Wellcome Genome Campus Cambridge England|European Bioinformat Inst EMBL EBI European Mol Biol Lab Cambridge England|Univ Cambridge Li Ka Shing Ctr Canc Res UK Cambridge Inst Cambridge England;

Wellcome Sanger Inst Wellcome Genome Campus Cambridge England|European Bioinformat Inst EMBL EBI European Mol Biol Lab Cambridge England|Univ Cambridge Cavendish Lab Theory Condensed Matter Grp Cambridge England;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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专利

1. Reelin is overexpressed in the liver and plasma of bile duct ligated rats and its levels and glycosylation are altered in plasma of humans with cirrhosis. [J] . Botella-Lopez A, de-Madaria E, Jover R, The international journal of biochemistry and cell biology . 2008,第4期

机译：胆管结扎大鼠的肝脏和血浆中reelin过表达，肝硬化患者血浆中reelin的水平和糖基化改变。
2. Human fetuin/alpha2HS-glycoprotein level as a novel indicator of liver cell function and short-term mortality in patients with liver cirrhosis and liver cancer. [J] . Kalabay L, Jakab L, Prohaszka Z, European journal of gastroenterology and hepatology . 2002,第4期

机译：人胎球蛋白/α2HS-糖蛋白水平可作为肝硬化和肝癌患者肝细胞功能和短期死亡率的新指标。
3. Studies on immunoproteasome in human liver. Part I: absence in fetuses, presence in normal subjects, and increased levels in chronic active hepatitis and cirrhosis. [J] . Vasuri F, Capizzi E, Bellavista E, Biochemical and Biophysical Research Communications . 2010,第2期

机译：人肝中免疫蛋白酶体的研究。第一部分：胎儿缺乏，正常人存在，慢性活动性肝炎和肝硬化水平升高。
4. High-throughput miniaturized fibrotic micro-niches for anti-fibrotic drug screening targeting collagen fiber-mediated mechanotransduction [C] . Zhifeng You, Lyu Zhou, Longwei Liu, Society for Biomaterials annual meeting and exposition . 2018

机译：高通量微型化纤维化微壁for，用于靶向胶原纤维介导的机械传导的抗纤维化药物筛选
5. 3D 31P MRSI of human liver: A spatially resolved study of normal and malignant tissue in response to stereotactic body radiation therapy. [D] . Jones, Scott. 2013

机译：人类肝脏的3D 31P MRSI：对立体定向放射疗法响应的正常和恶性组织的空间分辨研究。
6. Human serum fetuin A/α2HS-glycoprotein level is associated with long-term survival in patients with alcoholic liver cirrhosis comparison with the Child-Pugh and MELD scores [O] . László Kalabay, László Gráf, Krisztián Vörös, 2007

机译：酒精性肝硬化患者的血清人胎球蛋白A /α2HS-糖蛋白水平与长期生存相关并与Child-Pugh和MELD评分进行比较
7. Resolving the fibrotic niche of human liver cirrhosis at single-cell level [O] . P. Ramachandran, R. Dobie, J. R. Wilson-Kanamori, 2019

机译：单细胞水平分辨人肝肝硬化的纤维化利基

Resolving the fibrotic niche of human liver cirrhosis at single-cell level

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